Effective Activation of BKCa Channels by QO-40 (5-(Chloromethyl)-3-(Naphthalen-1-yl)-2-(Trifluoromethyl)Pyrazolo [1,5-a]pyrimidin-7(4 H)-one), Known to Be an Opener of KCNQ2/Q3 Channels

  • Pharmaceuticals (Basel). 2021 Apr 21;14(5):388. doi: 10.3390/ph14050388.
Wei-Ting Chang  1  2  3 ,  Sheng-Nan Wu  4  5  6
Affiliations
  • 1. Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
  • 2. Division of Cardiovascular Medicine, Chi-Mei Medical Center, Tainan 71004, Taiwan.
  • 3. Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan 71004, Taiwan.
  • 4. Department of Physiology, National Cheng Kung University Medical College, Tainan 70101, Taiwan.
  • 5. Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan 70101, Taiwan.
  • 6. Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan.
PMID: 33919092 DOI: 10.3390/ph14050388
Abstract

QO-40 (5-(chloromethyl)-3-(naphthalene-1-yl)-2-(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-7(4H)-one) is a novel and selective activator of KCNQ2/KCNQ3 K+ channels. However, it remains largely unknown whether this compound can modify any Other type of plasmalemmal ionic channel. The effects of QO-40 on ion channels in pituitary GH3 lactotrophs were investigated in this study. QO-40 stimulated CA2+-activated K+ current (IK(CA)) with an EC50 value of 2.3 μM in these cells. QO-40-stimulated IK(CA) was attenuated by the further addition of GAL-021 or paxilline but not by linopirdine or TRAM-34. In inside-out mode, this compound added to the intracellular leaflet of the detached patches stimulated large-conductance CA2+-activated K+ (BKCA) channels with no change in single-channel conductance; however, there was a decrease in the slow component of the mean closed time of BKCA channels. The KD value required for the QO-40-mediated decrease in the slow component at the mean closure time was 1.96 μM. This compound shifted the steady-state activation curve of BKCA channels to a less positive voltage and decreased the gating charge of the channel. The application of QO-40 also increased the hysteretic strength of BKCA channels elicited by a long-lasting isosceles-triangular ramp voltage. In HEK293T cells expressing α-hSlo, QO-40 stimulated BKCA channel activity. Overall, these findings demonstrate that QO-40 can interact directly with the BKCA channel to increase the amplitude of IK(CA) in GH3 cells.

Keywords
Ca2+-activated K+ current; OQ-40 (5-(chloromethyl)-3-(naphthalene-1-yl)-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-(4H)-one); hysteresis; large-conductance Ca2+-activated K+ channel; single-channel kinetics.
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